1. Field of the Invention
The present invention relates to a solid dosage form of an enteric solid dispersion produced for improving the solubility of a poorly soluble drug and a method for producing the same. In particular, the present invention relates to a solid dosage forms of an enteric solid, comprising the solid dispersion, that rapidly can be disintegrated and allow a drug to be dissolved, and a method for producing the same.
2. Description of the Related Art
Poorly soluble drugs have high crystallinity and extremely low solubility in water. Thus, bioavailability or internal absorption of preparations produced from these drugs is low, and thus there is the problem that the drug action is insufficient. As a technique for solving this problem, a solid dispersion has been developed in which molecules of a poorly soluble drug are dispersed in a high molecular weight carrier, such as a cellulose derivative, in an amorphous state.
Conventional solid dispersions are used as preparations in the form of capsules containing a solid obtained by spray-drying a cosolvent in which a poorly soluble drug and a carrier are dissolved, or in the form of fine granules or granules as they are. However, the form of tablets, which is a commonly solid dosage form, is most preferable because tablets are easily prescribed and used in a fixed dose, and easily handled and used by patients in use.
It is known that in the case of tablets produced from a solid dispersion powder, the porosity of the tablets is often lowered not only due to a reduced specific surface area, but also due to plastic deformation of amorphous drug molecules during a compression process and strong compressibility between high molecular weight carrier particles. This low porosity leads to slow permeation of water molecules into the tablets in administration, and to slow disintegration of the tablets, and thus the solid dispersion cannot exert its original effect of improving the solubility. Furthermore, the viscosity of a water-soluble high molecular weight substance or enteric high molecular weight substance serving as a carrier increases during hydration or dissolution, and thus a type of hydrogel layer is formed on the surface of the tablets during dissolution, so that water is further prevented from infiltrating.
As means for solving these problems, PCT Application Japanese Phase Publication No. 2005-517690 has proposed a tablet that contains a solid dispersion powder obtained by spray-drying, a disintegrant, and an excipient comprising porosigen. Furthermore, Japanese Patent Application Unexamined Publication No. 5-262642/1993 has proposed a powder in which a water-soluble high molecular weight base, and if necessary, an excipient and a disintegrant are added to a poorly soluble drug. However, a concentration-enhancing polymer and a water-soluble high molecular weight base, serving as carriers, are added in large amounts, and thus the viscosity of the polymer exhibited after administration increases. Thus, the drug release from the solid dosage form is poor, so that the dissolution speed of the drug tends to be lowered.
Furthermore, in the case of a solid dispersion powder obtained by spray-drying as in PCT Application Japanese Phase Publication No. 2005-517690, it is necessary that after the solid dispersion powder is mixed with the other ingredients, the mixture is compressed and pulverized for formation of a granulated powder for tableting. The particle size of the solid dispersion powder prepared by spray-drying in this manner is small, and thus when it is simply mixed with an excipient, segregation is caused, so that the ingredients become non-uniform in the powder for tableting. Moreover, this process makes the operation complicated, and the solid dispersion may be recrystallized in compression. Furthermore, the disintegrant is added after the solid dispersion has been prepared, and thus when the solid dispersion is aggregated and bonded in the tablet due to high bonding strength of the carrier, aggregation may be formed and dispersed in water during disintegration, lowering the solubility of the drug.
Furthermore, PCT Application Japanese Phase Publication No. 2005-517690 has a simple configuration in which the solid dispersion powder is prepared in advance from a poorly soluble drug and a concentration-enhancing polymer, and then the disintegrant and the excipient are physically mixed therewith, and therefore the obtained tablet is disintegrated even in the stomach. Thus, the solid dispersion with a larger specific surface area is exposed for a long time in digestive juice, so that the solubility may be lowered due to recrystallization of the dissolved drug.
Japanese Patent Application Unexamined Publication No. 2004-67606 has proposed a tablet using fine granules obtained by: spraying a solution containing itraconazole, which is a poorly soluble drug, a water-soluble polymer, and an enteric polymer, on a mixed powder of an excipient and a disintegrant; and granulating and drying the solvent. However, due to its poor disintegration, it takes as long as 360 minutes for the drug to be dissolved from the tablet. Thus, the disintegration of the tablet is not improved.
Hirasawa et al. (Journal of the Pharmaceutical Society of Japan, 124(1), 19-23 (2004)) has proposed a tablet produced from a product obtained by: loading an ethanol dispersion liquid as a binding fluid containing nilvadipine, which is a poorly soluble drug, crospovidone, and methylcellulose, into a mixed powder of materials such as lactose, methylcellulose, and low-substituted hydroxypropylcellulose; and agitating and granulating the resultant. However, in the ethanol solution containing nilvadipine, and crospovidone and methylcellulose, serving as carriers, the components are not dissolved. Thus, it seems that the solution functions only as an agent for dispersing and diluting amorphous nilvadipine, because a co-dissolved state is not obtained. In order to disperse amorphous drug molecules in a polymer serving as a carrier, it is necessary to obtain a co-dissolved state in a cosolvent in which these components are dissolved. Thus, it seems that the solid dispersion of amorphous nilvadipine described in Journal of the Pharmaceutical Society of Japan (124(1), 19-23 (2004)) does not have sufficient solubility. Furthermore, due to the influence of the water-soluble polymer, the disintegration is suppressed, and thus it may be difficult to obtain a preparation that can be rapidly dissolved.